Enantioselective, catalytic allylation of ketones and olefins

Abstract

Compounds containing a substituted or unsubstituted allyl group directly bound to a chiral carbon atom are prepared enantioselectively. Starting reactants are either chiral or achiral, and may or may not contain an attached allyloxycarbonyl group as a substituent. Chiral ligands are employed, along with transition metal catalysts. The methods of the invention are effective in providing enantioconvergent allylation of chiral molecules.

1. A method for synthesizing a compound containing a substituted or unsubstituted allyl group directly bound to a chiral carbon atom, comprising contacting an allyloxycarbonyl-substituted reactant with a transition metal catalyst in the presence of a chiral ligand, wherein the allyloxycarbonyl group is optionally substituted with one or more nonhydrogen substituents. 
     
     
       2. The method of  claim 1 , wherein the reactant is achiral. 
     
     
       3. The method of  claim 1 , wherein the reactant is chiral. 
     
     
       4. The method of  claim 3 , wherein the reactant comprises a racemic mixture of enantiomers. 
     
     
       5. The method of  claim 1 , wherein the method is enantioselective, such that the compound is provided in enantioenriched form. 
     
     
       6. The method of  claim 1 , wherein the optionally substituted allyloxycarbonyl group has the structure of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein R 13 , R 14 , R 15 , R 16  and R 17  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, and any two of R 13 , R 14 , R 15 , R 16  and R 17 , may be taken together and/or linked to another atom within the reactant to form a cyclic group. 
     
     
       7. The method of  claim 1 , wherein the reactant is an allyl enol carbonate. 
     
     
       8. The method of  claim 1 , wherein the reactant is a β-ketoester. 
     
     
       9. The method of  claim 1 , wherein the catalyst comprises a complex of a Group 6, 8, 9 or 10 transition metal. 
     
     
       10. The method of  claim 9 , wherein the transition metal is selected from Mo, W, Ir, Rh, Ru, Ni, Pt, and Pd. 
     
     
       11. The method of  claim 10 , wherein the transition metal is Pd. 
     
     
       12. The method of  claim 11 , wherein the catalyst comprises a complex of Pd(0). 
     
     
       13. The method of  claim 12 , wherein the catalyst is selected from: tris(dibenzylideneacetone)dipalladium(0); Pd(OC(0))CH 3 ) 2 ; PdCl 2 (R 23 CN) 2 ; PdCl 2 (PR 24 R 25 R 26 ) 2 ; [pd(η 3 -allyl)Cl] 2 ; and Pd(PR 24 R 25 R 26 ) 4 , wherein R 23 , R 24  R 25  and R 26  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl. 
     
     
       14. The method of  claim 13 , wherein the catalyst is tris(dibenzylideneacetone)dipalladium(0). 
     
     
       15. The method of  claim 11 , wherein the catalyst comprises a complex of Pd(II). 
     
     
       16. The method of  claim 15 , wherein the Pd(II) catalyst is further reduced to Pd(0) in situ. 
     
     
       17. The method of  claim 16 , wherein catalyst is selected from allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium (II), ([2S,3S]-bis[diphenylphosphino]butane)(η 3 -allyl)palladium(II) perchlorate, [S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η 3 -allyl)palladium(II) hexafluorophosphate, and cyclopentadienyl(η 3 -allyl)palladium(II). 
     
     
       18. The method of  claim 16 , wherein the catalyst is reduced with a reducing agent selected from NBu 4 OH, (n-Bu) 4 N + Ph 3 SiF 2   − , (n-Bu) 4 N + F − , 4-dimethylaminopyridine, NMe 4 OH (H 2 O) 5 , KOH/1,4,7,10,13,16-Hexaoxacyclooctadecane, EtONa, and trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, or mixtures thereof. 
     
     
       19. The method of  claim 1 , wherein the chiral ligand is monodentate or bidentate, and is substantially enantiopure. 
     
     
       20. The method of  claim 19 , wherein the chiral ligand has the structure of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein, in formula (IV),
 Q is a linker selected from hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, substituted heteroatom-containing hydrocarbylene, and a coordinated transition metal, and further wherein two or more substituents on Q may be linked to form a cycle; 
 X 1  and X 2  are independently selected from P, N, O, S, and As; 
 m and n are independently selected from 2, 3 and 4, and are chosen to satisfy the valency requirements of X 1  and X 2 , respectively; and 
 S 1  and S 2  are independently selected from hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, wherein two or more substituents on S 1  and/or S 2  may be linked to form a cycle, and further wherein S 1  and/or S 2  may form cycles such that X 1  and/or X 2  are incorporated into heterocycles. 
 
     
     
       21. The method of  claim 20 , wherein the chiral ligand is selected from oxazoles, phosphinooxazolines, imidazoles, phosphinoimidazolines, phosphines, phosphinopyridines, N-hetero carbenes, N-heterocyclic carbenes, and phosphinamines. 
     
     
       22. The method of  claim 21 , wherein the chiral ligand comprises an oxazolyl moiety. 
     
     
       23. The method of  claim 22 , wherein the chiral ligand is a phosphinooxazoline. 
     
     
       24. The method of  claim 21 , wherein the chiral ligand comprises a phosphinyl moiety. 
     
     
       25. The method of  claim 24 , wherein the chiral ligand is a bis-phosphine. 
     
     
       26. The method of  claim 21 , wherein the chiral ligand is an N-heterocyclic carbene. 
     
     
       27. The method of  claim 21 , wherein the chiral ligand is a phosphinamine. 
     
     
       28. The method of  claim 19 , wherein the chiral ligand has the structure of formula (V): 
       
         
           
           
               
               
           
         
       
       wherein, in formula (V):
 R 27 , R 28 , R 29 , R 30 , R 31 , and R 32  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, and any two of R 27 , R 28 , R 29 , R 30 , R 31 , and R 32  on adjacent atoms may be taken together to form a cycle; 
 X 3  is selected from —P(O)R 33 R 34 , —R 33 R 34 , —NR 33 R 34 , —OR 33 , —SR 33 , and —AsR 33 R 34 , wherein R 33  and R 34  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups; 
 X 4  is selected from NR 35  and O, wherein R 35  is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups; and 
 p is 0 or 1. 
 
     
     
       29. The method of  claim 1 , wherein the contacting is carried out in a solvent at a temperature in the range of about 0° C. to about 100° C. 
     
     
       30. The method of  claim 29 , wherein the contacting is carried out at a temperature in the range of about 20° C. to about 25° C. 
     
     
       31. The method of  claim 1 , wherein the metal from the catalyst is present in an amount ranging from about 1 mol % to about 20 mol % relative to the reactant. 
     
     
       32. The method of  claim 31 , wherein the amount is from about 1 mol % to about 10 mol %. 
     
     
       33. The method of  claim 1 , wherein the chiral ligand is present in an amount ranging from about 1 mol % to about 20 mol % relative to the reactant. 
     
     
       34. The method of  claim 33 , wherein the amount is from about 6 mol % to about 13 mol %. 
     
     
       35. The method of  claim 1 , wherein the compound is an α-allyl ketone and is synthesized in at least 60% enantiomeric excess. 
     
     
       36. The method of  claim 35 , wherein the compound is synthesized in at least 85% enantiomeric excess. 
     
     
       37. A method for enantioselectively allylating an olefinic substrate, comprising contacting the substrate with an allylating reagent in the presence of a transition metal catalyst and a chiral ligand under reaction conditions effective to provide a compound containing a substituted or unsubstituted allyl group directly bound to a chiral carbon, wherein the substrate has the structure of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, in formula (I):
 R 1 , R 2 , and R 3  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, wherein any two of R 1 , R 2 , and R 3  may be taken together to form a cycle; 
 Y is selected from —OR 4 , —NR 5 R 6 , and SR 7 , in which: 
 R 4  is selected from SiR 8 R 9 R 10 , SnR R 9 R 10 , and BR 11 R 12 , wherein R 8 , R 9 , and R 10  are independently selected from hydrocarbyl and substituted hydrocarbyl, R 11  and R 12  are independently selected from hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, and can optionally be taken together to form a cycle; 
 R 5  and R 6  are independently selected from Mg, Li, Zn, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, and R 5  and R 6  can optionally be taken together to form a cycle; and 
 R 7  is hydrogen or hydrocarbyl. 
 
     
     
       38. The method of  claim 37 , wherein the allylating reagent comprises a substituted or unsubstituted allyl group. 
     
     
       39. The method of  claim 38 , wherein the allylating reagent contains an attached allylic group that has the structure of formula (III): 
       
         
           
           
               
               
           
         
         wherein L is a leaving group, and R 18 , R 19 , R 20 , R 21  and R 22  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, and any two of R 18 , R 19 , R 20 , R 21  and R 22  may be taken together and/or linked to another atom within the allylating reagent to form a cyclic group. 
       
     
     
       40. The method of  claim 39 , wherein the allylating reagent is an allyl carbonate. 
     
     
       41. The method of  claim 40 , wherein the allylating reagent is an allyl alkyl carbonate or an allyl aryl carbonate. 
     
     
       42. The method of  claim 41 , wherein the allylating reagent is selected from bis(allyl) carbonate, allyl methyl carbonate, allyl phenyl carbonate, allyl ethyl carbonate, allyl 1-benzotriazolyl carbonate, and allyl chlorophenyl carbonate. 
     
     
       43. The method of  claim 39 , wherein R 18 , R 19 , R 20 , R 21  and R 22  are H. 
     
     
       44. The method of  claim 39 , wherein L is selected from halo, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, substituted or unsubstituted carbamato, and substituted or unsubstituted carbonato. 
     
     
       45. The method of  claim 44 , wherein the allylating reagent is an allyl halide. 
     
     
       46. The method of  claim 39 , wherein the allylating reagent is a cycloalkene. 
     
     
       47. The method of  claim 37 , wherein Y is —OR 9 , such that the olefinic substrate is an enol ether. 
     
     
       48. The method of  claim 47 , wherein R 9  is —SiR 8 R 9 R 10 , such that the olefinic substrate is a silyl enol ether. 
     
     
       49. The method of  claim 48 , wherein the method further comprises a desilylating reagent in an amount effective to provide for desilylation of the olefinic substrate. 
     
     
       50. The method of  claim 49 , wherein the desilylating agent is selected from (n-Bu) 4 N +Ph   3 SiF 2   − , MeLi, NaOEt, KOEt, KOtBu, CsF, and LiOMe. 
     
     
       51. The method of  claim 47 , wherein R 9  is SnR 8 R 9 R 10  such that the olefinic substrate is a stannyl enol ether. 
     
     
       52. The method of  claim 47 , wherein R 9  is BR 11 R 12 , such that the olefinic substrate is a boron enolate. 
     
     
       53. The method of  claim 37 , wherein Y is —NR 5 R 6 , such that the olefinic substrate is an enamine. 
     
     
       54. The method of  claim 53 , wherein the contacting results in the formation of an iminium ion. 
     
     
       55. The method of  claim 54 , further comprising hydrolyzing the iminium ion to form a ketone. 
     
     
       56. The method of  claim 37 , wherein the catalyst comprises a complex of a Group 6, 8, 9 or 10 transition metal. 
     
     
       57. The method of  claim 56 , wherein the transition metal is selected from Mo, W, Ir, Rh, Ru, Ni, Pt, and Pd. 
     
     
       58. The method of  claim 57 , wherein the transition metal is Pd. 
     
     
       59. The method of  claim 58 , wherein the catalyst comprises a complex of Pd(0). 
     
     
       60. The method of  claim 59 , wherein the catalyst is selected from: tris-(dibenzylideneacetone)dipalladium(0); Pd(OC(═O))CH 3 ) 2 ; PdCl 2 (R 23 CN) 2 ; PdCl 2 (PR 24 R 25 R 26 ) 2 ; [Pd(η 3 -allyl)Cl] 2 ; and Pd(PR 24 R 25 R 26 ) 4 , wherein R 23 , R 24 , R 25 , and R 26  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl. 
     
     
       61. The method of  claim 60 , wherein the catalyst is tris(dibenzylideneacetone)dipalladium(0). 
     
     
       62. The method of  claim 58 , wherein the catalyst comprises a complex of Pd(II). 
     
     
       63. The method of  claim 62 , wherein the Pd(II) catalyst is further reduced to Pd(0) in situ. 
     
     
       64. The method of  claim 63 , wherein catalyst is selected from allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium (II), ([2S,3S]-bis[diphenylphosphino]butane)(Θ 3 -allyl)palladium(II) perchlorate, [S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η 3 -allyl)palladium(II) hexafluorophosphate, and cyclopentadienyl(η 3 -allyl) palladium(II). 
     
     
       65. The method of  claim 63 , wherein the catalyst is reduced with a reducing agent selected from NBu 4 tOH, (n-Bu) 4 N + Ph 3 SiF − , (n-Bu) 4 N + F − , 4-dimethylaminopyridine, NMe 4 OH (H 2 O) 5 , KOH/1,4,7,10,13,16-Hexaoxacyclooctadecane, EtONa, and trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, or mixtures thereof. 
     
     
       66. The method of  claim 37 , wherein the chiral ligand is monodentate or bidentate, and is substantially enantiopure. 
     
     
       67. The method of  claim 66 , wherein the chiral ligand has the structure of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein, in formula (IV),
 Q is a linker selected from hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, substituted heteroatom-containing hydrocarbylene, and a coordinated transition metal, and further wherein two or more substituents on Q may be linked to form a cycle; 
 X 1  and X 2  are independently selected from P, N, O, S, and As; 
 m and n are independently selected from 2, 3 and 4, and are chosen to satisfy the valency requirements of X 1  and X 2 , respectively; and 
 S 1  and S 2  are independently selected from hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, wherein two or more substituents on S 1  and/or S 2  may be linked to form a cycle, and further wherein S 1  and/or S 2  may form cycles such that X 1  and/or X 2  are incorporated into heterocycles. 
 
     
     
       68. The method of  claim 67 , wherein the chiral ligand is selected from oxazoles, phosphinooxazolines, imidazoles, phosphinoimidazolines, phosphines, phosphinopyridines, N-heterocarbenes, N-heterocyclic carbenes, and phosphinamines. 
     
     
       69. The method of  claim 68 , wherein the chiral ligand comprises an oxazolyl moiety. 
     
     
       70. The method of  claim 69 , wherein the chiral ligand is a phosphinooxazoline. 
     
     
       71. The method of  claim 68 , wherein the chiral ligand comprises a phosphinyl moiety. 
     
     
       72. The method of  claim 71 , wherein the chiral ligand is a bis-phosphine. 
     
     
       73. The method of  claim 68 , wherein the chiral ligand is an N-heterocyclic carbene. 
     
     
       74. The method of  claim 68 , wherein the chiral ligand is a phosphinamine. 
     
     
       75. The method of  claim 66 , wherein the chiral ligand has the structure of formula (V) 
       
         
           
           
               
               
           
         
       
       wherein, in formula (V):
 R 27 , R 28 , R 29 , R 30 , R 31 , and R 32  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, and any two of R 27 , R 28 , R 29 , R 30 , R 31 , and R 32  on adjacent atoms may be taken together to form a cycle; 
 X 3  is selected from —P(O)R 33 R 34 , —PR 33 R 34 , —NR 33 R 34 , —OR 33 , —SR 33 , and —AsR 33 R 34 , wherein R 33  and R 34  are independently selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups; 
 X 4  is selected from NR 35  and O, wherein R 35  is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups; and 
 p is 0 or 1. 
 
     
     
       76. The method of  claim 37 , wherein the contacting is carried out in a solvent at a temperature in the range of about 0° C. to about 100° C. 
     
     
       77. The method of  claim 76 , wherein the contacting is carried out at a temperature in the range of about 20° C. to about 25° C. 
     
     
       78. The method of  claim 37 , wherein the metal from the catalyst is present in an amount ranging from about 1 mol % to about 20 mol % relative to the substrate. 
     
     
       79. The method of  claim 78 , wherein the amount is from about 1 mol % to about 10 mol %. 
     
     
       80. The method of  claim 37 , wherein the chiral ligand is present in an amount ranging from about 1 mol % to about 20 mol % relative to the substrate. 
     
     
       81. The method of  claim 80 , wherein the amount is from about 6 mol % to about 13 mol %. 
     
     
       82. The method of  claim 37 , wherein the compound is an α-allyl ketone and is provided in at least 60% enantiomeric excess. 
     
     
       83. The method of  claim 82 , wherein the compound is provided in at least 85% enantiomeric excess. 
     
     
       84. A method for catalytically and enantioconvergently synthesizing a compound, comprising contacting a mixture of isomers of a starting compound with a transition metal catalyst in the presence of a chiral ligand under reaction conditions sufficient to provide formation of a compound containing a carbon stereocenter, wherein the starting compound comprises a quaternary carbon stereocenter. 
     
     
       85. The method of  claim 84  wherein the mixture consists essentially of stereo isomers of a β-ketoester.